We believe that this study fully informs our understanding of neural mechanisms of behavioral change in aging human subjects by providing important data on the impact of genotype (in this case BDNF genotypes, including val66met and genotypes from another growth factor, NGF) on aging on transcriptional profiles in brain tissue, brain structure, neurocognition, and response to an exercise based treatment. This account will not only be mechanistic, but it will be fully translational in that it begins with 1. a molecular understanding of BDNF genotype modulate expression patterns in approximately 48000 cortical transcripts as determined by microarray profiling of human post mortem samples;2. examines the impact of age x BDNF genotypes on neuroanatomic volumes in structural MRI and neurocognition with an emphasis on episodic memory and medial temporal lobe structures and affect regulation;and includes 3. a proof of concept randomized trial examining the impact of physical exercise (designed to increase BDNF expression) and BDNF genotypes on cognitive endpoints. If the predictions in these studies are correct, we believe that we will have practical, personalized treatments to improve memory in older populations PUBLIC HEALTH RELEVANCE: This project aims to understand behavioral changes associated with aging from the standpoint of individual differences in genotype. To do this we assess the impact of different variants of a gene known to be important for memory on cognition, brain structure, and brain neurochemistry and how these interact with age. Importantly, we will also determine if the impact of a physical exercise program designed to improve mental fitness can be modulated by BDNF genotype.